We've already discussed drug names, generic and "brand" ones. But are there differences beyond the words? That's the topic of this week's Healthcare Triage.

(Intro)

Let's start with a story. When a drug first comes to market in the United States, the parent company can sell it exclusively under a brand name for a certain number of years.

This length of time depends on how many years are left on the drug's patent and the type of exclusivity granted at the time of approval by the FDA.

When the patent or exclusivity runs out, other manufacturers can begin making a generic. The generic product is sometimes cheaper than the brand name version.

This is probably why some generic products get a bad rap. There's this pervasive misperception that generic things are generally not as good as the brand because they're cheaper. While this may be true about those weird store-brand Froot Loops with no bird on the box, the same logic can't really be applied to generic drugs.

Here's why: before a company can manufacture and market a generic drug in the United States, it must submit an Abbreviated New Drug Application, or ANDA, to the FDA.

This application includes data proving the generic product is both pharmaceutically equivalent and bio-equivalent to the branded product.

Pharmaceutical equivalence means that the generic drug contains the same drug compound as the innovator drug, as well as having the same strength, same route of administration, and same dosage form.

To achieve bioequivalence, the generic product must have the same effect as the brand drug, meaning that the compound has the same action in the body in the same amount of time.

But make no mistake - just because the brand and generic have identical drug molecules, and are bioequivalent and pharmaceutically equivalent, does not mean that they are the same in every way.

That's because of excipients. Excipients are the inactive ingredients in a drug product, or the stuff that's not the active drug molecule.

Let's say you took a 10 milligram tablet of a popular allergy medication. If you weighed the tablet on a scale, it will definitely be heavier than 10 milligrams. That's because 10 milligrams is really tiny.

It would be nearly impossible to make a drug tablet so small, let alone expect someone to take it.

For example, a quarter teaspoon of table salt weighs like 1,500 mg. 10 mg is like less than 10 grains of kosher salt.

Some drugs use less than a milligram of active ingredient.

Therefore, drug manufacturers will use approved compounds, like lactose, starch, and microcrystalline cellulose, as diluents to bulk up tablets.

Other excipients might help tablets disintegrate in the digestive tract, or provide flavoring and coloring.

The list goes on and can get a little overwhelming when you start including dosage forms like inhalers, patches, creams, and ointments.

Generic and brand drugs will always have the same active ingredients, but their excipients may vary. One or the other may have slightly more or fewer types of inactive ingredients depending on their manufacturing processes.

Coloring agents usually also differ, so products can distinguish themselves, but remember, even though the entire ingredient list may not be exactly the same between brand and generic, the generic manufacturer must still prove to the FDA that their product is entirely bioequivalent.

If not, then an adjustment to the excipients may be warranted.

In the late 1960s, an outbreak of intoxication occurred in Australia among patients taking the anticonvulsant drug phenytoin.

In 87% of patients experiencing toxicity, drug levels measured in the blood were well beyond the therapeutic range, putting them at risk of side effects.

Many patients had changes in gait and some even experienced vomiting, double vision, and other abnormalities in mental function.

The good news is that the majority of people returned to normal once their dose was lowered. But why were patients that had been stable under anticonvulsant medication all of a sudden experiencing toxicity?

You guessed it - excipients. After evaluating the phenytoin capsules, investigators discovered that in 1967, one manufacturer had changed its diluent, or bulking agent, from calcium disulfate dehydrate to lactose.

The lactose formulation allowed the phenytoin to dissolve more readily from the capsule, leading to higher concentrations in the blood.

Thus, some patients began to experience toxic side effects, while others that were previously getting little benefit from the phenytoin had their seizures under control for the first time.

This incident shows that excipients aren't inert and justifies why it is so critical that brand and generic drugs be both pharmaceutically and bio-equivalent.

Today, the FDA and other regulatory bodies around the globe are really strict about all this. They aren't approving generic forms of drugs willy-nilly. In addition to being pharmaceutically equivalent and bio-equivalent, generic drugs must have the same strength, identity, purity, and quality as the branded product.

So the FDA regulates things, no surprises there, but why should we take their word for it? To the research!

A 2008 meta-analysis published in JAMA compared the clinical effectiveness of generic and brand name cardiovascular drugs. The study included 38 randomized controlled trials of 9 different subclasses of these medications.

Bioequivalence was seen in all studies of beta-blockers, antiplatelet agents, statins, ACE inhibitors, alpha-blockers, anti-arrhythmic agents, and warfarin.

It was seen in 10 of 11 randomized controlled trials of diuretics and 71% of calcium channel blockers - so not perfect - but these differences were minor and did not impact clinical outcomes.

Overall, the aggregate effect of the meta-analysis indicated that there were no significant differences between brand and generic drugs.

The same study also examined editorials and commentaries discussing the interchangeability of brand and generic cardiovascular drugs. Of 43 editorials, more than half expressed a negative view of generic drugs.

Let's look deeper. Some drugs have what's known as a narrow therapeutic index, meaning that the drug is only effective within a very small dosage range; too little and the drug will have no effect, too much and the drug could cause harm.

One such drug is the blood thinner Coumadin, also known by its generic name, warfarin. Not everyone responds to warfarin in the same way, so those taking it have their blood monitored regularly, so that appropriate dose adjustments can be made.

Because of this, physicians and pharmacists are hesitant to interchange the brand and generic versions of Coumadin and drugs like it, but what do the data say?

A review article published in 2011 in the Journal of Pharmacotherapy examined 5 randomized controlled trials and 6 observational studies comparing outcomes when switching patients from Coumadin to generic warfarin.

The observational studies suggested that those switching between brand and generic should be monitored more closely, so perhaps there's a reason to be more cautious about switching between brand and generic warfarin.

In the randomized controlled trials, though, there were no significant differences reported at all. No studies showed that the branded drug was more effective than the generic.

Similar results were seen in systematic reviews of anti-epileptic drugs.

Even though national regulatory bodies require a mountain of data proving bioequivalence and independent studies have shown that generics are just as effective as innovator drugs, there's still this lingering perception among some practitioners that generic drugs aren't as good.

A survey of 506 physicians in the United States revealed that as many as 23% had negative opinions on the efficacy of generic drugs, and those over the age of 55 were more than 3 times as likely to believe that.

Another survey looked at both physicians and pharmacists. While 11.8% of doctors believed that generic drugs were less effective than the brand product, only 2.3% of pharmacists shared this opinion.

Why? Here's what Rachel thought.

Pharmacists spend a lot of time in school learning about the chemical nature of drugs and how excipients work in drug products, perhaps resulting in a higher degree of confidence in a well-formulated generic.

Conversely, physicians may be more likely to hear first-hand accounts of patients being unhappy with the generic, making them less likely to prescribe it in the future.

Ignoring this has consequences. A 2014 study compared adherence to statin therapies in patients that were started on either the brand or generic drug.

A significantly higher number of patients started on generics were compliant with their medication regimen, and those taking generics had an 8% reduction in hospitalization for acute coronary syndrome or stroke.

Why? Cause generics cost less. People are more likely to stick to stuff that's not as expensive for them.

This matters! A chemical compound is a chemical compound, and as long as bioequivalence is assured, brand and generic drugs should give the same results.

There may be good reason to be cautious when switching back and forth between different formulations of certain narrow therapeutic index drugs, but for the vast majority of small molecular drugs, there's no difference. Don't get hung up on the labels.

Healthcare Triage is supported in part by viewers like you through patreon.com, a service that allows you to support the show through a monthly donation. Your support helps us make this bigger and better.

We'd especially like to thank our research associate Cameron Alexander and our first-ever Surgeon Admiral Sam. Thanks Cameron! Thanks Sam!

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